The traditional antiviral approach is to design drugs targeting viral proteins. It tends to have a relatively narrow spectrum of action and frequently need to be replaced with novel drugs since high mutation rate of viral genome causes drug resistance. In addition, there are limited numbers of viral proteins that can be targeted by drugs. Since host factors and genetic pathways play important roles in determining the susceptibility and resistance to viral infections and the outcome of viral pathogenesis. Functional Genetics Inc. (FGI) proposed research is novel in that it is aimed at discovering the host genes and genetic pathways that is required for viral pathogenesis, to determine their potential as therapeutic targets for viral infection and to develop agents against viral infection targeting the host factors and pathways. Antiviral drugs that targeting cellular proteins would not be constrained by the same limitation of transitional approach and could be used as a component of combination therapies against a broad spectrum of viruses. The rapid mutation rate and pandemic potential of Influenza presents a major threat to the national security and public health. FGI's initial goals are to apply its novel genetic approach RHKO (random Homozygous Knockout) to discover mammalian genes and genetic pathways required for infection and pathogenesis of influenza. Specifically , we will use RHKO to random inactivate or activate genes in Influenza susceptible cells, screen cells that acquired resistance to influenza infection as a result of RHKO, identify and isolate host genes and to determine the pathways involved in the replication cycle and pathogenesis of influenza virus. Functional validation and characterization of the host genes allows us to determine their roles in the pathogenesis of Influenza and other related viruses, and to evaluate their potential as therapeutic and preventive targets. Finally to screen known inhibitors of host factors and to develop new drugs against influenza infection targeting host genes identified from this genetic screening. Using Influenza as a model system, FGI's long term objective is the development of host-oriented therapeutics (HOT) against broad-spectrum viral pathogens. [unreadable] [unreadable]